The design, synthesis, and evaluation of coumarin ring derivatives of the novobiocin scaffold that exhibit antiproliferative activity.
Novobiocin, a known DNA gyrase inhibitor, binds to a nucleotide-binding site located on the Hsp90 C-terminus and induces degradation of Hsp90-dependent client proteins at approximately 700 microM in breast cancer cells (SKBr3). Although many analogues of novobiocin have been synthesized, it was only recently demonstrated that monomeric species exhibit antiproliferative activity against various cancer cell lines. To further refine the essential elements of the coumarin core, a series of modified coumarin derivatives was synthesized and evaluated to elucidate structure-activity relationships for novobiocin as an anticancer agent. Results obtained from these studies have produced novobiocin analogues that manifest low micromolar activity against several cancer cell lines.
Donnelly
Alison C
AC
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, Kansas 66045-7563, USA.
Mays
Jared R
JR
Burlison
Joseph A
JA
Nelson
John T
JT
Vielhauer
George
G
Holzbeierlein
Jeffrey
J
Blagg
Brian S J
BS
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D009281:Naphthalenes / Q000737:chemistry; D009675:Novobiocin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry
D003374:Coumarins; D009281:Naphthalenes; D011804:Quinolines; D009675:Novobiocin; C031721:naphthalene; C030123:coumarin; C037219:quinoline